Internalization of receptors from the cell surface regulates diverse physiological processes from the rate of nutrient uptake to the timescale of signaling events. Cells control the number of specific receptors on their surfaces by balancing the rate of receptor delivery with the rate of uptake by endocytosis. The established view is that internalization of receptors is controlled by specific biochemical binding interactions between receptor internalization motifs and clathrin adaptor proteins. Because many different receptors share recognition motifs for a small set of adaptor proteins, receptors which bind to the same adaptor protein are thought to compete with one another for entry into endocytic structures. However, variants of the same recognition motif have different affinity for the same adaptor protein. How do receptors with different affinities for the same adaptor protein compete with one another for internalization? To address this question, we constructed a series of model receptors with decreasing affinity for the adaptor protein AP2. As expected, internalization of a model receptor with high affinity for AP2 was reduced when co-expressed with a competing receptor of similar affinity for AP2. Surprisingly, internalization of a model receptor with low affinity for AP2 was unaffected by a competing receptor with high affinity for AP2. These findings suggest that weakly internalized receptors are protected against competition with strongly internalized receptors. This protection could arise from the small fraction of the endocytic structure area occupied by the weakly internalized receptor, requiring the competing receptor to saturate nearly all available space within the structure to generate a competitive effect. Given the critical role of internalization in receptor signaling, this effect may serve as a protection mechanism to prevent strongly internalized receptors from interfering with the cell’s ability to process signals from weakly internalized receptors.

Clathrin-mediated endocytosis of weakly internalized receptors is protected against competition

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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